Method of omeprazole preparation

ABSTRACT

The invention involves a method of preparation of omeprazole by a reaction of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole with peroxyacetic acid in a two-phase water and chlorinated organic solvent medium, in alkaline pH, subsequent separation of water and organic phases after the reaction and isolation of omeprazole from organic phase.

This application is a 371 of PCT/SK97/00008 filed Sep. 8, 1997.

TECHNICAL FIELD

The invention solves a method of preparation of a pharmaceuticalsubstance5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole,which is known under its generic name omeprazole.

DESCRIPTION OF THE RELATED ART

According to the Swedish patent SE 4231, omeprazole is prepared byoxidation of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1Hbenzimidazole, (further referred to as the compound I) withm-chloroperoxybenzoic acid.

In the PCT application published under WO 91/118895 is described animproved method of preparation of omeprazole by oxidation of thecompound I again with m-chloroperoxybenzoic acid, but in an alkalinemedium.

Also other patents provide for preparation of omeprazole by oxidation ofthe compound I with different oxidizing agents.

In the European patent EP 484 265 preparation of omeprazole by oxidationof the compound I with hydrogen peroxide in the presence of molybdenumsalts as catalysts is described.

The European patent EP 302 720 has patented preparation of omeprazole byoxidation of the compound I with hydrogen peroxide using vanadiumcatalysts. The British patent GB 2 239 453 describes preparation ofomeprazole by photo-chemic oxidation of the compound I.

Other way of omeprazole preparation is oxidation of the compound I bymagnesium peroxyphatalate provided for in the European patent EP 533264, and oxidation by iodosobenzene or iodosotoluene described in theSpanish patent ES 539 793. The Spanish patent ES 543 816 describespreparation of omeprazole by oxidation of the compound I withm-chloroperoxybenzoic acid powder.

Disadvantages of these preparation methods are that prepared omeprazoleis contaminated by starting substance and there are many side productsproduced during the reactions, including especially5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphonyl]-1H-benzimidazole as a product offollowing omeprazole oxidation.

The procedures mentioned above utilize relatively expensive oxidizingreagents.

The possible using of peroxyacetic acid in the preparation of compoundsof this type is only generally mentioned, together with many otheroxidizing agents (see, e.g. Houben-Weyl Vol. E11/Part 1, p. 702-752, EP533 264, EP 298 440 . . . ).

The most frequently described oxidizing reagent in the preparation ofomeprazole from the compound I is m-chloroperoxybenzoic acid.

The object of the present invention is the use of peroxyacetic acid asan oxidizing agent in the preparation of omeprazole from the compound I.Surprisingly, we have found, that the use of peroxyacetic acid as anoxidizing agent instead of m-chloroperoxybenzoic acid in the preparationof omeprazole provides a crude product of unexpectedly high purity.Practically, the product is not contaminated by hardly removablesulphone impurity,5-methoxy-2-[[(4-metoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphonyl]-1H-benzimidazole,as in the case of omeprazole preparation by means ofm-chloroperoxybenzoic acid.

The object of the present invention is to provide a method for thepreparation of omeprazole, which utilizes a very cheap oxidizing agent.Furthermore, a such method for preparation of omeprazole is provided, inwhich neither toxic components nor components requiring expensiveliquidation are formed, as in the case of other oxidizing reagentsdescribed in connection with the preparation of omeprazole (e.g.m-chloroperoxybenzoic acid, molybdenum and vanadium catalysts, magnesiumperoxyphthalate, iodosobenzene and iodosotoluene).

When the reaction is completed, omeprazole is simply isolated from theorganic phase, and acetic acid formed from the oxidizing agent remainsin the aqueous phase and is liquidated in very easy and cheap way.

SUMMARY OF THE INVENTION

The mentioned disadvantages of the presently known methods for theomeprazole preparation are eliminated by a method of preparation ofomeprazole according to the present invention, which comprises thereaction of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole(the compound I) with peroxyacetic acid in a two-phase water andchlorinated organic solvent medium, in alkaline pH, subsequentseparation of water and organic phases after the reaction and isolationof omeprazole from organic phase.

The peroxyacetic acid is used in amount of 0,8 to 2,0 molar equivalentsto the compound I, advantageously in the amount of 0,9 to 1,1 molarequivalent.

The pH of reaction mixture during the reaction is maintained from 7,1 to9,5. The best is, however, to work with the pH ranging from 8,0 to 8,5.

The temperature of reaction mixture is maintained during the reactionfrom 0° C. to 25° C., the best range from 1° C. to 5° C.

As chlorinated organic solvent can be used dichloromethane, chloroform,or dichloroethane, using of dichloromethane is preferable.

When the reaction is completed, organic and water phases are separated,and omeprazole is isolated from the organic phase.

The advantage of the process according to the present invention is thatvery cheap peroxyacetic acid is used for the oxidation. Anotheradvantage of the process according to the present invention is thatomeprazole is isolated from the organic phase after completion of thereaction, and the acetic acid formed from the peroxyacetic acid duringthe reaction remains in the aqueous phase. This waste aqueous phasecontains no toxic components and can be liquidated in an easy and cheapway.

The principal advantage of the process according to the presentinvention is that the prepared omeprazole is of high purity andpractically contains no initial substance as well as the hardlyremovable sulphone impurity,5-methoxy-2-[[(4-metoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphonyl]-1H-benzimidazole.

The present invention will be further illustrated in practicalembodiments, without being limited to them.

EXAMPLES OF CARRYING OUT THE INVENTION Example No. 1

3,29 g (0,01 mol) of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazoleis dissolved in 50 ml of dichloromethane and pH is adjusted to 8,0-8,5by adding water solution of sodium carbonate. Then, 3,46 g (0,01 mol) ofperoxyacetic acid is added in drops at temperature of the reactioncompound from 0° C. to 5° C., and pH is maintained by adding watersolution of sodium carbonate between 8,0 to 8,5. The reaction mixture isstirred for 120 minutes. Afterwards, the dichloromethane layer isseparated and scrubbed with water and brine, dried with sodium sulphateand densified on a vacuum evaporator till it is dry. The yield is 3,27 g(94,8%) of omeprazole.

Example No. 2

3,29 g (0,01 mol) of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazoleis dissolved in 50 ml of chloroform and pH is adjusted to 7,1-7,6 byadding water solution of sodium carbonate. Then, 2,76 g (0,008 mol) ofperoxyacetic acid is added in drops at temperature of the reactionmixture from 20° C. to 25° C., and pH is maintained by adding watersolution of sodium carbonate between 7,1 to 7,6. The reaction mixture isstirred for 120 minutes. Afterwards, the chloroform layer is separatedand scrubbed with water and brine, dried with sodium sulphate anddensified on a vacuum evaporator till it is dry. The yield is 2,58 g(74,8%) of omeprazole.

Example No. 3

3,29 g (0,01 mol) of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazoleis dissolved in 50 ml of dichloroethane and pH is adjusted to 9,0-9,5 byadding water solution of sodium carbonate. Then, 6,92 g (0,02 mol) ofperoxyacetic acid is added in drops at temperature of the reactionmixture from 5° C. to 10° C., and pH is maintained by adding watersolution of sodium carbonate between 9,0 to 9,5. The reaction mixture isstirred for 120 minutes. Afterwards, the dichloroethane layer isseparated and scrubbed with water and brine, dried with sodium sulphateand densified on a vacuum evaporator till it is dry.

The yield is 2,76 g (80,1%) of omeprazole.

Example No. 4

3,29 g (0,01 mol) of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazoleis dissolved in 50 ml of dichloromethane and pH is adjusted to 8,0-8,5by water solution of sodium carbonate. Then, 3,81 g (0,011 mol) ofperoxyacetic acid is added in drops at temperature of the reactionmixture from 10° C. to 15° C., and pH is maintained by adding watersolution of sodium carbonate between 8,0 to 8,5. The reaction mixture isstirred for 120 minutes. Afterwards, the dichloromethane layer isseparated and scrubbed with water and brine, dried with sodium sulphateand densified on a vacuum evaporator till it is dry.

The yield is 3,15 g (90,2%) of omeprazole.

Industrial Utilisation

Omeprazole is used in pharmaceutical industry as a pharmaceuticalsubstance in human medicine.

What is claimed is:
 1. The method of omeprazole preparationcharacterised by reaction of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazolewith peroxyacetic acid in a two-phase water and chlorinated organicsolvent medium, in pH ranging from 7.1 to 9.5, subsequent separation ofwater and organic phases after the reaction and isolation of omeprazolefrom organic phase.
 2. The method according to claim 1, characterized byusing 0.8 to 2.0 molar equivalents, of peroxyacetic acid to5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole.
 3. The methodaccording to claim 1, characterised by maintaining the temperature ofreaction mixture in the range from 0° C. to 25° C.
 4. The methodaccording to claim 1, characterised by using dichloromethane, chloroformor dichloroethane as chlorinated organic solvent.
 5. The methodaccording to claim 2, characterised by using 0.9 to 1.1 molar equivalentof peroxyacetic acid to 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole.6. The method according to claim 1, characterised by maintaining thealkaline pH of the reaction mixture in the range from 8.0 to 8.5.
 7. Themethod according to claim 3, characterised by maintaining thetemperature of reaction mixture in the range from 1° C. to 5° C.
 8. Themethod according to claim 4, characterised by using dichlormethane aschlorinated organic solvent.
 9. The method of omeprazole preparationcharacterised by reaction of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazolewith peroxyacetic acid in a two-phase water and chlorinated organicsolvent medium, in pH ranging from 8.0 to 8.5, subsequent separation ofwater and organic phases after the reaction and isolation of omeprazolefrom organic phase.